rs142883891

Variant names:

• chrX-108591181-C-A
• rs142883891
• NM_033380.3:c.1289C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108591181-C-A
• chrX-108591181-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033380.3(COL4A5):​c.1289C>A​(p.Ala430Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,208,648 control chromosomes in the GnomAD database, including 12 homozygotes. There are 2,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A430T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., 152 hem., cov: 23)
  • Exomes 𝑓: 0.0053 (10 hom. 1862 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.89
• Publications: 7 publications found

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P, ClinGen
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_033380.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00821501).
• BP6: Variant X-108591181-C-A is Benign according to our data. Variant chrX-108591181-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00417 (469/112598) while in subpopulation NFE AF = 0.00582 (310/53233). AF 95% confidence interval is 0.00529. There are 2 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.1289C>A	p.Ala430Asp	missense	Exon 20 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.1289C>A	p.Ala430Asp	missense	Exon 20 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.1289C>A	p.Ala430Asp	missense	Exon 20 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.113C>A	p.Ala38Asp	missense	Exon 4 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.1289C>A	p.Ala430Asp	missense	Exon 20 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 469 AN: 112547 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00977

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00218

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00330

GnomAD2 exomes AF: 0.00465 AC: 851 AN: 182887 AF XY: 0.00507

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00527 AC: 5778 AN: 1096050 Hom.: 10 Cov.: 30 AF XY: 0.00514 AC XY: 1862 AN XY: 362324

African (AFR) AF: 0.000532 AC: 14 AN: 26338

American (AMR) AF: 0.00148 AC: 52 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00909 AC: 176 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00427 AC: 231 AN: 54046

European-Finnish (FIN) AF: 0.00989 AC: 401 AN: 40526

Middle Eastern (MID) AF: 0.00165 AC: 5 AN: 3026

European-Non Finnish (NFE) AF: 0.00553 AC: 4656 AN: 841438

Other (OTH) AF: 0.00529 AC: 243 AN: 45960

GnomAD4 genome AF: 0.00417 AC: 469 AN: 112598 Hom.: 2 Cov.: 23 AF XY: 0.00437 AC XY: 152 AN XY: 34782

African (AFR) AF: 0.000707 AC: 22 AN: 31109

American (AMR) AF: 0.00158 AC: 17 AN: 10730

Ashkenazi Jewish (ASJ) AF: 0.00977 AC: 26 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00219 AC: 6 AN: 2738

European-Finnish (FIN) AF: 0.0135 AC: 83 AN: 6156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00582 AC: 310 AN: 53233

Other (OTH) AF: 0.00326 AC: 5 AN: 1533

Alfa AF: 0.00456 Hom.: 178

Bravo AF: 0.00337

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00588 AC: 17

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00699 AC: 47

ExAC AF: 0.00500 AC: 607

EpiCase AF: 0.00562

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	X-linked Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Benign	0.51	T
Polyphen		0.0090	B
Vest4		0.070
MVP		0.56
MPC		0.45
ClinPred		0.018	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.37
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142883891; hg19: chrX-107834411;